New‐onset sarcoidosis in a patient with long COVID

Key Clinical Message Long COVID, often following SARS‐CoV‐2 infection, may stem from sustained inflammation, overlapping with autoimmune diseases like sarcoidosis. Though specific treatments lack, this link could shape future diagnostic and therapeutic methods.


| INTRODUCTION
Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, is a complex medical condition that persists in selected patients after a SARS-CoV-2 infection. 13][4] This condition is characterized by over 200 associated symptoms, including hair loss, fever, fatigue, post-exertional malaise, cognitive difficulties, mood disorders, sleep disturbances, headaches, palpitations, chest pain, and shortness of breath. 1,5PASC symptoms can vary from mild to severe, significantly impacting daily activities and work obligations.Severe symptoms usually peak within the first 28 days post-infection, while mild to moderate symptoms can persist for weeks afterward. 6ccording to the National Center for Health Statistics, the estimated prevalence of long COVID in the United States is 15.7%, and it is more commonly observed in females.This is likely influenced by biological factors like the X chromosome and sex hormone differences, alongside a pronounced innate and adaptive immune response that moderates acute COVID-19 in females but increases susceptibility to inflammatory and autoimmune diseases. 7,8Long COVID also often coexists with conditions such as diabetes, obesity, and chronic pulmonary or renal disease. 7One prevailing hypothesis to explain long COVID is an ongoing and sustained inflammatory response. 9,10ollowing SARS-CoV-2 infection, various rheumatological and autoimmune diseases have been reported.These manifestations are diverse, ranging from organ-specific to systemic autoimmune and inflammatory responses. 11,12rgan-specific manifestations include cutaneous vasculitis, immune thrombocytopenic purpura, transverse myelitis, and Guillain-Barré syndrome. 11,12On the other hand, systemic autoimmune and inflammatory conditions encompass systemic vasculitis, multisystem inflammatory syndrome, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. 11,12][15][16][17][18][19][20][21][22][23][24] Sarcoidosis is a multi-systemic inflammatory disorder characterized by the formation of non-caseating granulomas, which can affect different organs, including the lungs, regional lymph nodes, skin, liver, central nervous system, and eyes.It can affect individuals of all ages and races. 25The underlying cause of sarcoidosis remains unknown, but it is believed that various factors, including infections, contribute to its development and pathogenesis. 26e report the case of a previously healthy White male who developed long COVID and mediastinal lymphadenopathy after acute SARS-CoV-2 infection.ndobronchial ultrasound-guided transbronchial needle aspiration revealing non-caseating granulomas and high plasma ACE levels consistent with sarcoidosis.

| CASE HISTORY/EXAMINATION
On December 24, 2020, a previously healthy 35-year-old white male presented to the office with shortness of breath, body aches, cough, nasal congestion, and with a temperature of 37.5°C.On presentation, he was found to be vitally stable and saturating at 95% on ambient air.Laboratory analyses were unremarkable, and a chest x-ray showed bilateral patchy airway opacities.A SARS-CoV-2 polymerase-chain reaction (PCR) from a nasopharyngeal swab was positive, confirming the diagnosis of mild COVID-19.The patient was discharged on albuterol nebulizer, prednisone 40 mg daily for 5 days, and levofloxacin 750 mg daily for 5 days.
Following his initial episode of COVID-19, the patient continued to experience persistent fatigue.In February 2021, he experienced recurrent chest congestion, tightness of the lungs, a productive cough, and a fever of 38.7°C.A SARS-CoV-2 PCR from a nasopharyngeal swab resulted negative, and he was empirically treated for suspected atypical pneumonia with azithromycin 500 mg on the first day, followed by 250 mg for 4 days.Two months later, he experienced another episode of generalized body aches, night sweats, and fevers up to 39.2°C, without cough, shortness of breath, or chest pain, which persisted for 2 weeks.Another SARS-CoV-2 PCR from a nasopharyngeal swab was performed, resulting in a positive result for the second time.
After the second episode of COVID-19, the patient continued to experience body aches, headaches, brain fog, difficulty concentrating, insomnia, fatigue, dizziness, tinnitus, short-term memory issues, and intermittent subjective fevers with exertional malaise that was severe at times, preventing him from working or performing activities of daily living.Subsequent laboratory studies showed elevation in inflammatory markers, including an erythrocyte sedimentation rate of 23 mm/h (reference range: 0-15 mm/h) and a C-reactive protein level of 3.1 mg/dL (reference range: ≤0.5 mg/dL).However, other studies, including a complete blood count, electrolytes, blood cultures, creatinine kinase, acute hepatitis B and C antibody panels, urinalysis, were all negative.Angiotensinconverting enzyme (ACE) levels were normal (49 U/L, reference range: 9-67 U/L).Chest x-ray showed no abnormalities (Figure 1).

INVESTIGATIONS, AND TREATMENT
He was referred to sleep medicine and was found to have mild sleep apnea, for which conservative management with weight loss was recommended.He was also evaluated by a neurologist, who recommended magnetic resonance imaging (MRI) of the brain, auditory canal, and whole spine, which showed normal findings.Given the F I G U R E 1 Initial chest x-ray.Initial chest x-ray shows a normal cardiomediastinal silhouette and no signs of infiltrates, effusion, or pneumothorax.negative workup, he was diagnosed with long COVID and started on physical therapy, modafinil, and bupropion.In August 2022, he experienced a third episode of mild COVID-19 for which he received treatment with nirmatrelvir/ritonavir (Paxlovid).
The patient's persistent symptoms led to his referral to the Stanford Post-Acute COVID-19 Syndrome clinic in November 2022.During evaluation, a chest x-ray was performed, revealing bilateral hilar enlargement that raised suspicion of lymphadenopathy (Figure 2).Subsequent computed tomography (CT) of the chest confirmed diffuse mediastinal and bilateral hilar bulky adenopathy (Figure 3A), accompanied by scattered pulmonary nodules bilaterally (Figure 3B).Laboratory studies indicated elevated serum calcium levels of 10.5 mg/dL (reference range: 8.6-10.3mg/ dL), with a corrected calcium level of 9.9 mg/dL, adjusted for an albumin level of 4.8 g/dL.Furthermore, the patient exhibited low parathyroid hormone levels (10 pg/mL, reference range: 16-77 pg/mL) and elevated ACE levels (114 U/L).In December 2022, the patient received a clinical diagnosis of pulmonary sarcoidosis following a transbronchial fine needle aspiration lymph node biopsy that showed non-caseating granulomas (Figure 4).

| OUTCOME AND FOLLOW-UP
Treatment was initiated with a prednisone taper, starting at 40 mg for 2 weeks, followed by 30 mg for 2 weeks, 20 mg for 2 weeks, 10 mg for 2 weeks, and then 10 mg for 4 weeks, resulting in an improvement of almost all long COVID symptoms and normalization of ACE levels (61 U/L) after several weeks of follow-up.

| DISCUSSION
We report a case of a previously healthy White male who developed PASC following to an acute COVID-19 episode in December 2020.Initially, his chest imaging and ACE levels were normal.However, as time progressed, the patient's symptoms persisted, worsened, and were eventually associated with mediastinal lymphadenopathy and elevated plasma ACE levels.An endobronchial ultrasound-guided transbronchial needle aspiration later revealed non-caseating granulomas, indicative of sarcoidosis.After a regimen of systemic steroids, the patient's long COVID symptoms completely resolved, and his ACE levels returned to normal.The pathophysiological mechanisms underlying long COVID remain elusive.][29] Other research suggests that long COVID may be linked to persistent reservoirs of SARS-CoV-2 in tissues and the reactivation of viruses like Epstein-Barr virus (EBV) and human herpesvirus-6. 300][31][32][33][34] Additionally, long COVID has been associated with a host of conditions, including cardiovascular, thrombotic, and cerebrovascular diseases, type 2 diabetes, myalgic encephalomyelitis/chronic fatigue syndrome, dysautonomia, and autoimmune disorders. 29,30These conditions may share a similar pathogenesis with long COVID. 30Notably, autoimmune phenomena consistently emerge as significant in theories explaining long COVID.6][37] One such study highlighted that patients with a prior COVID-19 diagnosis had a 42.63% increased likelihood of developing autoimmunity. 370][41][42][43] Although some viral infections have well-documented autoimmune effects, the links between other common viruses and autoimmune disorders are difficult to prove. 42Pandemics offer a unique opportunity to understand this link and the underlying pathogenesis, primarily due to their large sample sizes and the heightened vigilance of the medical community for rare outcomes. 43arcoidosis is an idiopathic granulomatous multisystem disorder characterized by dense epithelioid non-necrotizing lesions, predominantly affecting the lungs and lymph nodes, accompanied by varying degrees of lymphocytic inflammation. 25,44It affects all races, ethnicities, and genders with a higher prevalence among females and typically emerging in young to  middle-aged adults, peaking around years in men and 50-60 years in women. 45The later diagnosis age in women compared to men may relate to menopause impacting lung function and the premenopausal protective effect of estrogen against sarcoidosis. 46While the exact cause remains elusive, specific environmental and occupational exposures have been linked to elevated disease rates.These include exposure to metals and silica, workers exposed to debris on September 11, 2001, firefighters, and certain infections. 26,47,48Infections with many organisms have been correlated with sarcoidosis, including Cutibacterium acnes, mycobacteria, and different viruses such as human herpesvirus-8 (HHV-8), EBV, and hepatitis C. 26,49,50 So far, 15 cases, including ours, have been reported with patient-level data linking sarcoidosis to COVID-19 (Table 2). 51Out of these, 10 were diagnosed a month or longer after their initial COVID-19 diagnosis.While some of these cases experienced symptoms associated with long COVID, such as fatigue, cough, and malaise, only our case had a PASC score of 12, aligning with the symptom-based PASC definition proposed by Thaweethai et al. 1 Among these cases, six developed stage ≥2 sarcoidosis, [15][16][17][18]24 with one showing hepatic involvement, 14 and another receiving a sarcoidosis diagnosis during the acute COVID-19 episode. 23Furthermore, six presented with stage 1 sarcoidosis, 16,[19][20][21][22][23] with two experiencing neurosarcoidosis, 21,22 and four displaying cutaneous manifestations, including two cases of erythema nodosum.13,14,16,19 The median age of these patients was 49 years (IQR 35-54 years), with 53% of the patients being male.The reporting of race was infrequent, predominantly involving White individuals (13%). Meiastinal lymph node enlargement on imaging was observed in 60% of cases, while non-necrotizing or non-caseating granulomas on biopsy were present in 87%.Elevated ACE levels were documented in only four cases. Aditionally, 60% of the cases received systemic steroids for treatment.[13][14][15][16][17][18][19][20][21][22][23][24] The reported cases and a large cohort study provides compelling evidence to support an association between SARS-CoV-2 and sarcoidosis.[13][14][15][16][17][18][19][20][21][22][23][24]37 Certainly, there are comparable immune response pathways in both sarcoidosis and convalescent COVID-19 patients that contribute to granuloma formation. Thse include disruption of the renin-angiotensin system, elevated CD4/CD8 ratio in bronchoalveolar lavage fluid, accumulation of multinucleated giant cells in lung tissue, polarization of Th17 cells into Th1 cells, increased production of type II interferon (IFN-γ), dysregulated autophagy, upregulation of cytokines, and reduced PD-1 expression. 43,48Furthermore, clinical manifestations such as mild fever, fatigue, joint pain, cognitive disorders, and weight loss exhibit overlapping characteristics among patients with both sarcoidosis and long COVID.48 In conclusion, long COVID is a multifaceted condition that persists in certain individuals following a SARS-CoV-2 infection, with symptoms extending beyond the acute phase and potentially giving rise to various newonset conditions.The reported case highlights the intricate interplay between long COVID and sarcoidosis, shedding light on their overlapping clinical features and immunological pathways.The emergence of SARS-CoV-2 has brought to the forefront new evidence suggesting a connection between infections and sarcoidosis.When managing patients with long COVID, healthcare providers should prioritize assessing for autoimmune conditions, as this approach could potentially offer tailored treatment options.

F
I G U R E 2 Follow-up chest x-ray.Follow-up chest x-ray reveals bilateral hilar enlargement, indicative of lymphadenopathy.F I G U R E 3Computed tomography of the chest without contrast.Computed tomography of the chest reveals diffuse mediastinal and bilateral hilar adenopathy (A), with bulky hilar nodes measuring up to 2.7 cm on the right and 1.7 cm on the left.The largest mediastinal nodes are 1.7 cm in the right paratracheal area and 2.2 cm in the prevascular region.Additionally, pleural nodules measuring 3 mm are noted bilaterally, accompanied by scattered small bilateral lung nodules up to 5 mm, including probable intrapulmonary lymph nodes (B).

T A B L E 1 4
List of autoimmune disorders associated with SARS-CoV-Lymph node biopsy.Station seven lymph node biopsy.Photomicrograph of lymph node tissue displaying lymphocytes, epithelioid histiocytes, and multinucleated giant cells consistent with a non-necrotizing granuloma typical of sarcoidosis.Hematoxylin and eosin, bar = 100 μm.T A B L E 2 Reported cases of sarcoidosis following COVID-19.